Effects of Metformin and Vildagliptin on the Rat’s Heart with Chronic Myocardial Infarction

Abstract

Heart failure (HF) is the most common complication and a major cause of morbidity and mortality in patients with myocardial infarction (MI). It has been know that Enalapril, an angiotensin coverting enzyme (ACE) inhibitor, is a first-line drug for MI patients, which has been demonstrated to decrease risks of heart failure progression post-MI. Previous studies showed that enalapril could improve cardiac function and decrease cardiac remodeling including cardiac fibrosis and cardiac hypertrophy. Nowadays, clinical evidence shows that both metformin and vildagliptin, which have been used to treat type II diabetic patients, have cardioprotective effects. Data from several studies in the past decade suggested that these drug could decreased cardiac remodeling and improved cardiac function in both animal and clinical studies in non-diabetic and diabetic patients with MI. Despite cardioprotective effects of metformin and vildagliptin having been demonstrated, comparing data between these drugs in chronic MI has not been well studied. Therefore, we aimed to determine the effects of metformin and vildagliptin on the cardiac remodeling in chronic MI rats. We hypothesized that treatments with combined metformin and enalapril and combined vildagliptin and enalapril can improve cardiac remodeling and function compared with enalpril alone. To test the hypothesis, 36 male Wistar rats were induced chronic MI by left anterior descending coronary artery ligation. Then, all rats were randomly divided to receive vehicle, enalapril (10 mg/kg, once daily), metformin (15 mg/kg, twice day), vildagliptin (3 mg/kg, once daily), combined metformin and enalapril, or combined vildagliptin and enalapril, for 8 weeks. At the end of study, plasma malondialdehyde (MDA), heart rate variability (HRV), cardiac remodeling, cardiac function, Bcl-2, Bax, Connexin43, Caspase3, transforming growth factor-beta (TGF-β), phosphorylated-p38 (p-p38) and phosphorylated-p44/42 (p-p44/42) protein expressions were investigated. Our study demonstrated that chronic MI rats developed cardiac symphathovagal imbalance, increased oxidative stress levels, cardiac fibrosis in peri-infarct area, and LV dysfunction. Our study demonstrated that enalapril, vildagliptin, combined metformin and enalapril, and combined vildagliptin and enalapril could improve cardiac function as well as decrease plasma MDA levels, low frequency and high frequency ratio, cardiac fibrosis in non infarct area in association with decreased p-p44/42 expression, whilst there was no difference in infarct size among all groups. Treatment with metformin alone did not alter cardiac remodeling and cardiac function in chronic MI rats. Only treatment with enalapril could decrease Bax/Bcl-2 protein expression whilst all pharmacological treatments in this study did not alter Bcl-2, Bax, p-p38, TGF-β, connexin 43, caspase3 expression and cardiomyocyte hypertrophy. We conclude that treatments with vildagliptin, enalapril, combined metformin and enalapril, and combined vildagliptin and enalapril can improve cardiac function and attenuate cardiac fibrosis via decreased p-p44/42 expression in chronic MI rats. However, combining either metformin or vildagliptin with enalapril does not have additional cardioprotective effects compared to enalapril alone.